Nature: Nuclear transcriptional regulator in the paired-box family expressed during organogenesis of the thyroid gland, kidney, and Müllerian tract.
Gene and structure: Chromosomal localization 2q13, Molecular weight of the unprocessed precursor 48 kDa, of five isoforms 31-42 kDa.
Occurrence and function: PAX8 is a transcription factor crucial to the organogenesis and development of the thyroid gland, urogenital tract, placenta and inner ear. In the thyroid, PAX8 is a master gene that regulates maintenance of the differentiated thyroid follicular cell phenotype, where it controls and activates the transcription of the main proteins responsible for the functional activity of follicular cells such as thyroglobulin, thyroperoxidase and sodium/iodide symporter. In the developing kidney PAX8 is important for renal vescicle formation. PAX8 regulates the expression of the WT1 gene.
Positive (+): Follicular and papillary thyroid carcinoma are virually always PAX8 positive (while anaplastic carcinoma is positive in most cases and medullary thyroid carcinoma negative). PAX8 is also found in almost all cases of ovarian serous, endometrioid, transitional and clear cell carcinoma (while mucinous carcinoma is positive in a minor number of cases), and endometrial carcinoma.
Mostly positive (+/-): PAX8 is found in most cases of all types of renal cell carcinoma and in oncocytoma as well as in thymic tumours.
Mostly negative (-/+): PAX8 is also found in a minor number of lung squamous cell carcinoma. Sporadic cases of gastrointestinal adenocarcinomas, uterine cervical neoplasia, seminoma and malignant mesothelioma are reported positive. There are conflicting data on the positivity in urothelial carcinoma.
Negative (-): Adenocarcinomas of lung and breast have consistently been reported negative.
Neuroendocrine tumours have been reported to be positive, but this staining is most likely due to cross-reaction with PAX6.
PAX8 appears to be currently the most sensitive and specific marker for renal cell carcinoma and ovarian non-mucinous carcinoma. It has to be noted that several antibodies (especially polyclonal) developed for visualization of PAX8 cross-reacts with PAX2, PAX5 or PAX6. Caution has to be execised when interpreting slides stained with these antibodies.
Kidney and Fallopian tube are both recommended as positive tissue controls for PAX8. In kidney, optimally calibrated protocols must provide an at least weak to moderate, distinct nuclear staining reaction in the majority of epithelial cells of the proximal and distal renal tubules, loops of Henle, collecting ducts, and the parietal epithelial cells of Bowman’s capsule. A weak to moderate cytoplasmic staining reaction in the same cells can be expected. In Fallopian tube, the protocol must be calibrated to provide an at least weak to moderate, distinct nuclear staining in the majority of the ciliated epithelial cells and a strong nuclear staining of the intercalated secretory epithelial cells. A weak cytoplasmic staining in the intercalated secretory epithelial cells can be expected and must be accepted. Internal observations show that inadequate fixation (too short time / delayed) in formalin can reduce epitope availability in low-level PAX8 expressing structures.
Tonsil can be used as negative tissue control for PAX8, as no staining should be seen in e.g. squamous epithelial cells and lymphocytes (positive nuclear staining in B-cells indicate cross reaction with PAX5).